Tag Archives: tacrolimus

A recent retrospective study (C Efe et al. Clin Gastroenterol Hepatol 2017; 15: 1950-6) examined both mycophenolate mofetil (MMF, n=121) and tacrolimus (TAC, n=80) as second-line therapies for autoimmnue hepatitis with a median followup of 62 months. Patients were divided into two groups. The first group (n=108) had a complete response to steroids/azathioprine but had side effects. The second group (n=93) were nonresponders to steroids/azathioprine. Overall, the cohort examined patients as young as 7 years and as old as 76 years.

Key findings:

No significant difference in complete response noted in 69.4% of MMF-treated compared with 72.4% in TAC-treated patients.

In group 1 patients (responders to azathioprine), MMF and TAC maintained biochemical remission in 91.9% and 94.1% respectively.

In group 2 (prior nonresponders), TAC-treated patients had a complete response rate of 56.5% compared with 34% for MMF-treated patients (P=.029).

Liver-related deaths and transplantation occurred with similar rates: MMF 13.2% compared with TAC 10.3%. With each treatment, 10 patients withdrew from treatment due to side effects.

My take: In this study, both agents were effective in those who changed due to side effects. However, tacrolimus-treated patients had a higher response among prior nonresponders.

A total of 174 children and adolescents were treated with adalimumab as their first anti-TNF therapy…The mean age at the time of Crohn’s disease diagnosis was 13 years and, on average, they started adalimumab at 14.5 years of age…

At 3 months after adalimumab was started, all 174 were still on the medication, and 69-71% were in steroid-free remission

At 6 months after adalimumab was started, of the 174 who had a clinic visit, 95% were still on the medication, and 75-77% were in steroid-free remission

At 12 months after adalimumab was started, of the 154 who had a clinic visit, 94% were still on the medication, and 79-80% were in steroid-free remission

At 24 months after adalimumab was started, of the 71 who had a clinic visit, 97% were still on the medication, and 91-94% were in steroid-free remission

At 36 months after adalimumab was started, of the 39 who had a clinic visit, 80-86% were still on the medication, and 81-86% were in steroid-free remission

No positive or negative effect on remission was seen with concomitant immunomodulator therapy. However, the number of patients studied during the retrospective analysis is too small to detect all but the greatest impact of this approach.

Surgical complications were common (n=13 in 7 subjects) and included stoma obstruction, stoma prolapse, and resection of ischemic bowel.

One notable feature regarding this cohort was that 50% were 5 or younger when diagnosed with IBD.

The authors conclude that a diverting ileostomy can induce clinical stability and allow time to clarify diagnosis.

A Assa et al. JPGN 2017; 65: 293-98. In this study involving findings from 234 patients extracted from the ImageKids database (prospective multicenter cohort), the authors found that pediatric patients with perianal Crohn’s disease have a greater inflammatory burden; however, this was driven mainly by those who had fistulizing disease.

L Lian et al. Clin Gastroenterol Hepatol 2017; 15: 1226-31. This retrospective study from the Cleveland Clinic compared outcomes of endoscopic balloon dilation (EBD) (n=176) or surgery (n=131) for Crohn’s disease-related strictures (1998-2013). Patients who had EBD had an “average time to surgery delayed by 6.45 years.” Immediate success rate for EBD was 91.3%; the perforation rate was 1.1%.. Ultimately, 52% of patients who had EBD required surgery. Earlier surgery lowered the risk of further surgery but also was associated with significant perioperative complications. In the operative group, 8.8% of patients experienced complications, mainly intra-abdominal abscesses and enterocutaneous fistula. Thus, in the right hands and with careful selection, EBD may be useful.

I Lawrance et al. Clin Gastroenterol Hepatol 2017; 15: 1248-55. This study reported the results of 11 patients who received rectal tacrolimus for resistant ulcerative proctitis. Dosing: The concentration of tacrolimus was 0.5 mg/mL and 3 mL was administered twice a day.Clinical response, using the Mayo Clinic score, was achieved in 73% of tacrolimus subjects compared with 10% (n=1) of placebo-treated subjects. Mucosal healing at week 8 was noted in 73% of tacrolimus-treated patients, as well.

For Crohns’ disease , Vedolizumab also works in Crohn’s disease, but it takes time (Sands et al: Gastroenterology 2014 147:618‐627)

Off-label does not equate to experimental! pg 199:

FDA Statement: The FD&C Act does not, however, limit the manner in which a physician may use an approved drug. Once a product has been approved for marketing, a physician may prescribe it for uses or in treatment regimens or patient populations that are not included in approved labeling. Such “unapproved” or, more precisely, “unlabeled” uses may be appropriate and rational in certain circumstances, and may, in fact, reflect approaches to drug therapy that have been extensively reported in medical literature.

A recent study shows that once daily tacrolimus can be effective in patients who have been stable following liver transplantation (LT) (Liver Transplantation 2013; 19: 529-33).

In this retrospective, single center study with 394 adult LT patients, the authors examined the results of conversion to once daily dosing of tacrolimus. Patient demographics noted an mean age of 53 years & mean time post-transplant was 74 months.

Criteria for conversion:

At least 6 months posttransplant

No rejection in >3 months

Tacrolimus bid was changed to the same total daily dose at once a day and then modified based on levels.

Results after a 24 month followup:

358 of 394 were able to maintain once a day dosing. 6 patients had been converted to cyclosporine, 14 patients had stopped all calcineurin inhibitors, 16 patients had returned to BID dosing.

While tacrolimus has been considered a potential option for refractory Crohn’s, data on its usage are sparse, mostly small retrospective studies. Another small retrospective study from the Mayo clinic provides data from their experience with 24 adult patients who were treated with tacrolimus for a median of 4 months (Inflamm Bowel Dis 2013; 19: 1107-11).

17 (71%) of study participants were female and their median age was 38 years. 18 (75%) had ileocolonic disease. All patients were either intolerant or unresponsive to at least one anti-TNFα agent. Most patients received concurrent therapy: thiopurines (58%), methotrexate (8%) and antibiotics (46%).

Results:

67% responded to tacrolimus and 21% achieved a steroid-free remission.

Patients with trough levels of 10 to 15 ng/mL had the highest response (86%) and remission (57%).

54% of patients in this series required surgery within a median of 10 months after starting tacrolimus.

Of the patients who achieved remission (n=5), 2 were transitioned to immunomodulator therapy to minimize long-term toxicity. 1 patient did well after stopping all therapy during a 6 month followup. 1 patient stopped treatment due to paresthesias and 1 patient continued therapy for 2.5 years.

The study does not describe the use of antibiotics for the prevention of Pneumocystisjiroveci pneumonia.